EFFECT OF KETANSERINE IN CYCLOSPORINE-INDUCED RENAL DYSFUNCTION IN RATS

Cyclosporine (CsA)-treated female Wistar rats, in dose of 37.5 mu M (4 5 mg)/ kg/day for 7 days, exhibited significantly decreased creatinine clearance (Ccr), and provoked body weight loss (BWL), which is consis tent with the development of nephrotoxicity (NT). Urine volume (V) did not change and proteinuria (PU) was not provoked. These changes were associated with significantly diminished ratios of urinary PGE(2)/TXB( 2) and 6kPGF(1 alpha)TXB(2) excretions. Light-microscopic (LM) section s of rat kidneys showed that all kidneys were affected but the lesions (mainly diffuse vacuolization) were reversible. When CsA-treated anim als were pretreated with ketanserine (KTS), which antagonizes (a) the direct vasoconstrictor effect of serotonin (5-HT), and (b) the amplify ing effects of 5-HT on other vasoactive substances (such as noradrenal ine (NA), alpha(1)-receptors, histamine, H-2 receptors, and prostaglan din F-2 alpha), Ccr and urine volume significantly increased, BWL was partially prevented and the ratios of urinary PGE(2)/TXB(2) and 6kPGF( 1 alpha)TXB(2) excretions were significantly enhanced. LM sections sho wed that only 5 of 9 rats were affected but the lesions were of less i mportance. These observations indicate that the NT induced by CsA in o ur studies was mediated by 5-HT, a potent vasoconstrictor agent, and b y the metabolites of arachidonic acid. However, other vasoactive agent s and additional mechanisms could also be implicated.